Hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and related compounds

ABSTRACT

The present invention relates to hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and related compounds, of formula &lt;CHEM&gt;  wherein R&lt;1&gt; is H, alkyl, or benzyl; R is a group of the formula &lt;CHEM&gt; wherein Y is H, H or O, R&lt;2&gt; is H, alkyl, or phenyl, and Z is O or S; wherein Z of the group of the formula &lt;CHEM&gt; is bound to either the A- or B-position of the heteroaromatic nucleous; X is H, halogen, alkoxyl, alkyl, or trifluoromethyl; and n is 1, 2 or 3; a process for their preparation and intermediates thereof. The compounds of the invention are able to relieve memory dysfunction, particularly dysfunctions associated with decreased cholinergic activity such as those found in Alzheimer&#39;s disease and can, therefore, be used as medicaments.

The present invention relates to hexahydroquinobenzoxazepines andrelated compounds. More particularly, the present invention relates tohexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and -thiazepines offormula 1 ##STR1## wherein R¹ is H, alkyl, or benzyl; R is a group ofthe formula ##STR2## wherein Y is H, H or O, R² is H, alkyl, or phenyl,and Z is O or S; wherein Z of the group of the formula ##STR3## is boundto either the A- or B-position of the heteroaromatic nucleus; X is H,halogen, alkoxy, alkyl, or trifluoromethyl and n is 1, 2, or 3; thepharmaceutically acceptable salts thereof; and the optical isomersthereof, which are useful for relieving memory dysfunction, for example,memory dysfunction such as that associated with reduced cholinergicfunction in Alzheimer's disease, alone or in combination with adjuvants.

Subgeneric to the hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines andthiazepines of the present invention are compounds wherein:

(a) Z of the group of the formula ##STR4## is bound to the A-position ofthe heteroaromatic nucleus; Y is H, H or O and n is 2; and

(b) Z of the group of the formula ##STR5## is bound to the B-position ofthe heteroaromatic nucleus; Y is H, H or O and n is 2.

The present invention also relates to amines of formula 2 ##STR6##wherein R¹ is H, alkyl or benzyl; R³ is a H, alkyl, a group of theformula CH₂ CHR² Hal wherein R² is hydrogen, alkyl, or phenyl and Hal ischloro, bromo, or iodo, or a group of the formula CHR² CO₂ R⁵ wherein R²is as above and R⁵ is H or alkyl; Z is O or S; X is H, halogen, alkoxy,alkyl, or trifluoromethyl; n is 1, 2, or 3; the group ZR³ is bound toeither the A- or B-position of the heteroaromatic nucleus, which areuseful as intermediates for the preparation of the presenthexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines and thiazepines and forrelieving memory dysfunction.

As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 10 carbon atoms such asmethyl, ethyl, n-propyl, tert-butyl, hexyl, octyl, decyl and the like;the term "alkoxy" refers to a monovalent substituent which consists ofan alkyl group linked through an ether oxygen and having its freevalence bond from the ether oxygen such as methoxy, ethoxy, isopropoxy,tert-butoxy, hexoxy, octoxy, decoxy and the like; the term "halogen"refers to a member of the family fluorine, chlorine, bromine or iodine.The term "lower" as applied to any of the aforementioned groups refersto a group having a carbon skeleton containing up to and including 6carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipodes may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof of the compounds disclosed and claimed herein and the formulasof the compounds shown herein are intended to encompass all possibleoptical isomers of the compounds so depicted.

The novel hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepines of the presentinvention are synthesized by the processes illustrated in ReactionSchemes A, B, and C.

To gain entry into the2,3,4a,5,6,7-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine system,i.e., to elaborate a quinobenzoxazepine 5, a9-amino-1,2,3,4-tetrahydoracridin-1-ol 3, the synthesis of which isdescribed in G. M. Shutske, et al., Journal of Medicinal Chemistry, 32,1805 (1989), is condensed with a haloalkanol 9

    HalCH.sub.2 CHR.sup.2 OH                                   9

wherein R² is hydrogen, alkyl, or phenyl and Hal is chloro, bromo, oriodo to provide a 1-(2-haloalkoxy)-1,2,3,4-tetrahydro-9-acridinamine 4which is cyclized to a 2,3,4a,5,6,7-hexahydrobenzoxazepine 5. SeeReaction Scheme A.

The condensation is performed by contacting a tetrahydroacridinol 3 witha haloalkanol 9 in the presence of a mineral acid, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid, oran organic acid, for example methanesulfonic acid, para-toluenesulfonicacid, or trifluoroacetic acid, trifluoroacetic acid being preferred.While the condensation temperature is not narrowly critical, thereaction is preferably performed within the range of about 0° C. toabout 50° C., a reaction temperature of about 25° C. being mostpreferred.

The cyclization of a 1-(2-haloalkyoxy)acridinamine 4 is carried out inthe presence of an alkali metal alkoxide in an ethereal solvent. Amongalkali metal alkoxides there may be mentioned lithium, sodium, andpotassium methoxide, ethoxide, 1- and 2-propoxide, 1,1-dimethylethoxide,and the like. Potassium 1,1-dimethylethoxide (potassiumtertiary-butoxide) is preferred. Among ethereal solvents there may bementioned diethyl ether, 1,2-dimethoxyethane, dioxane, 2-methoxyethylether, and tetrahydrofuran. Tetrahydrofuran is preferred. Thecyclization proceeds at a reasonable rate at about 25° C., higherreaction temperatures within the range of about 25° to about 50° C. andlower reaction temperatures within the range of about 0° to 25° C. maybe employed. A cyclization temperature of about 25° C. is preferred.

Alternatively, a2,3,4a,5,6,7-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine 5 isobtained by condensing 3 wherein R¹ is hydrogen with an alkylhydroxyalkanoate of formula 10.

    HOCHR.sup.2 CO.sub.2 R.sup.5                               10

wherein R² is hydrogen, alkyl, or phenyl; and R⁵ is alkyl, to afford analkyl [(9-amino-1,2,3,4-tetrahydroacridin-1-yl)oxy]acetate 6 wherein R¹is hydrogen which is cyclized to a 1,3,4a,5,6,7-hexahydrobenzoxazepinone7 wherein R¹ is hydrogen and reduced to a2,3,4a,5,6,7-hexahydrobenzoxazepine 5 wherein R¹ is hydrogen oralkylated to a 1-alkyl-1,3,4a,5,6,7-hexahydro-2H-benzoxazepinone 8wherein R¹ is alkyl and reduced to a1-alkyl-2,3,4a,5,6,7-hexahydrobenzoxazepine 5 wherein R¹ is alkyl.

The condensation is conducted by a process substantially similar to themethod hereinbeforedescribed for the conversion of 3 to 4. In thisinstance, sulfuric acid and a condensation temperature of about 0° C.are the preferred mineral acid and reaction temperature. Thecondensation is performed in an ethereal solvent such as tetrahydrofuranor neat, i.e., in the absence of a solvent. It is preferred to performthe condensation in the absence of a solvent.

The cyclization of an alkyl [9-aminotetrahydroacridin-1-yl]acetate 6 toa hexahydroquinobenzoxazepinone 7 is also accomplished by the processhereinbeforedescribed for the conversion of 4 to 5.

The reduction is conducted by contacting a hexahydroquinobenzoxazepinone7 or 8 with an alkali metal aluminum hydride in an ethereal solvent.Included among alkali metal aluminum hydrides are lithium, sodium, andpotassium aluminum hydride. Included among ethereal solvents are diethylether, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, andtetrahydrofuran. Lithium aluminum hydride and tetrahydrofuran are thepreferred reducing agent and solvent, respectively. While the reductionproceeds readily under these conditions, a promoter such as aluminumchloride may be utilized. The reduction also proceeds readily at about25° C. Elevated temperatures within the range of about 25° to 50° C. andreduced temperatures within the range of about 0° to about 25° C. may beemployed.

Similarly, a 2,3,4a,5,6,7-hexahydroquinobenzthiazepine 15 wherein R¹ ishydrogen is fabricated by condensing an aminoacridinol 3 wherein R¹ ishydrogen with an alkyl thioglycolate of formula 11

    HSCHR.sup.2 CO.sub.2 R.sup.5                               11

wherein R² is hydrogen, alkyl, or phenyl; and R⁵ is alkyl to provide analkyl [(9-amino-1,2,3,4-tetrahydroacridin-1-yl)thio]acetate 12 whereinR¹ is hydrogen which is cyclized to a1,3,4a,5,6,7-hexahydrobenzthiazepinone 13 wherein R¹ is hydrogen andreduced to a 2,3,4a,5,6,7-hexahydrobenzthiazepinone 15 wherein R¹ ishydrogen by utilizing processes substantially similar to those employedfor the conversion of 3 to 8 via 6 and 7. A2,3,4a,5,6,7-hexahydroquinobenzothiazepine 15 wherein R¹ is alkyl isprepared by alkylation of 1,3,4a,5,6,7-hexahydrobenzthiazepine 13wherein R¹ is hydrogen to a1-alkyl-1,3,4a,5,6,7-hexahydro-2H-benzthiazepin-2-one 14 wherein R¹ isalkyl followed by reduction to a1-alkyl-2,3,4a,5,6,7-hexahydro-1H-benzthiazepine 15 wherein R¹ is alkylby processes also substantially similar to those described for theconversion of 7 to 8 to 5 of Scheme A. See Reaction Scheme B.

The hydrolysis of a benzthiazepinone 13 to[(tetrahydroacridinyl)thio]acetic acid 16 is effected by conventionalmethods. For example, treatment of an aqueous solution of abenzthiazepinone 13 with hydrochloric acid at ambient temperature gavean acid 16. See Reaction Scheme B.

To gain entry into the1,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine system,i.e., to construct a quinobenzoxazepine 21, an8-hydroxy-1,2,3,4-tetrahydro-9-acridinamine 17 is condensed with analkyl haloalkanoate 22

    HalCHR.sup.2 CO.sub.2 R.sup.5                              22

wherein R² and R⁵ are as hereinbeforedescribed and Hal is bromo, chloro,or iodo to yield an alkyl[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]acetate 18 which iscyclized to a1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one 19and either reduced to a2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine 21 whereinR¹ is hydrogen or first alkylated to a1-alkyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one20 and then reduced to a2-alkyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine 21wherein R¹ is alkyl. See Reaction Scheme C.

The condensation is accomplished by contacting a hydroxyacridinamine 17with a alkyl haloalkanoate 22 in the presence of an alkali metalcarbonate or bicarbonate condensing agent such as, for example, lithium,sodium, or potassium carbonate or bicarbonate in a dipolar aproticsolvent such as, for example, dimethylacetamide, dimethylformamide,hexamethylphosphoramide or dimethylsulfoxide to provide a[(tetrahydroacridinyl)oxy]acetate 18. Potassium carbonate anddimethylformamide are the preferred condensing agent and solvent. Thecondensation proceeds at a reasonable rate at about 25° C. Higherreaction temperatures (about 25° to about 50° C.) and lower reactiontemperatures (about 0° to about 25° C.) may be utilized.

The cyclization of a [(tetrahydroacridinyl)oxy]acetate 18 to ahexahydroquinobenzoxazepinone 19 is effected by processes essentiallythe same as those hereinbeforedescribed for the cyclization of 4 to 5.

Likewise, the reduction of a hexahydroquinobenzoxazepinone 19 to a2,3,9,10,11,12-hexahydroquinobenzoxazepinone 21 (R¹ is hydrogen) or thereduction of a 2-alkylhexahydroquinobenzoxazepinone 20 to a2-alkyl-2,3,9,10,11,12-hexahydro-1H-quinobenzoxazepine 21 (R¹ is alkylof benzyl) is accomplished by methods essentially the same as thoseemployed for the reduction of 7 to 8. Alternatively, the reductions of19 to 21 and 20 to 21 are accomplished by diborane in an etherealsolvent, e.g., tetrahydrofuran, 2-methoxyethyl ether or dioxane, at areduction temperature of from about 0° to about 50° C. Tetrahydrofuranand a reaction temperature of about 25° C. are preferred.

The alkylation is conducted by contacting ahexahydroquinobenzoxazepinone 19 with a haloalkane of formula 23

    HalR.sup.1                                                 23

wherein R¹ is an hereinbeforedefined in an ethereal solvent, namely,diethyl ether, 2-methoxyethyl ether, 1,2-dimethoxyethane, dioxane ortetrahydrofuran, or a dipolar aprotic solvent, namely dimethylformamide,dimethylacetamide, hexamethylphosphoramide or dimethylsulfoxide, in thepresence of a base, namely, an alkali metal alkoxide such as lithium,sodium or potassium methoxide, ethoxide, 1- or 2-propoxide or1,1-dimethylethoxide. The preferred solvents are tetrahydrofuran anddimethylsulfoxide. The preferred alkali metal alkoxide is potassium1,1-dimethyethoxide (potassium tertiary-butoxide). The reduction iscarried out at a temperature between about 0° to about the refluxtemperature of the reaction mixture. When tetrahydrofuran is used as thesolvent, it is preferred to perform the alkylation at either about 25°C. or about the reflux temperature of the reaction mixture. Whendimethylformamide is employed, it is preferred to carry out thealkylation at about 25° C.

A 2,3,4a,5,6,7-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine 5 is alsoprepared by the process outline in Reaction Scheme D. For example,treatment of 9-amino-3,4-dihydroxyacridin-1(2H)one 27 (R¹ and X arehydrogen), the preparation of which is described in U.S. Pat. No.4,631,286, issued Dec. 23, 1986, with the styrene oxide indimethylformamide provides3,4-dihydro-9-[(2-hydroxy-2-phenyethyl)amino]-1(2H)acridinone 28 (R¹ andX are hydrogen and R² is phenyl), which is reduced with lithium aluminumhydride to1,2,3,4-tetrahydro-9-[(2-hydroxy-2-phenylethyl)amino]-1-acridinol 29 (R¹and X are hydrogen and R² is phenyl) and cyclized by means of sulfuricacid/trifluoro acetic acid to 5 (R¹ and X are hydrogen and R² is phenyl.

The starting material for synthesis of the ultimate2,3,9,10,11,12-hexahydro-1H-quinobenzoxazepines 21, i.e., an8-hydroxy-1,2,3,4-tetrahydro-9-acridinamine 17, is obtained bycondensing a readily available 6-methoxyanthranilonitrile 24 withcyclohexanone 25 in the presence of zinc chloride in nitrobenzene toafford an 8-methoxy-1,2,3,4-tetrahydro-9-acridinamine 26 which isdealkylated to 17 by means of boron tribromide in dichloromethane, asshown below. ##STR7##

The related compounds of the present invention may be prepared from theappropriate precursors by method essentially the same as thosehereinbeforedescribed.

The benzoxazepines, -thiazepines, and tetrahydroacridinamines andrelated compounds of the present invention are useful as agents for therelief of memory dysfunction, particularly dysfunctions associated withdecreased cholinergic activity such as those found in Alzheimer'sdisease. Relief of memory dysfunction activity of the instant compoundis demonstrated in the dark avoidance assay, an assay for thedetermination of the reversal of the effects of scopolamine inducedmemory deficits associated with decreased levels of acetylcholine in thebrain. In this assay, three groups of 15 male CFW mice were used--avehicle/vehicle control group, a scopolamine/vehicle group, and ascopolamine/drug group. Thirty minutes prior to training, thevehicle/vehicle control group received normal saline subcutaneously, andthe scopolamine/vehicle and scopolamine/drug groups received scopolaminesubcutaneously (3.0 mg/kg, administered as scopolamine hydrobromide).Five minutes prior to training, the vehicle/vehicle control andscopolamine/vehicle groups received distilled water and thescopolamine/drug group received the test compound in distilled water.

The training/testing apparatus consisted of a plexiglass boxapproximately 48 cm long, 30 cm high and tapering from 26 cm wide at thetop to 3 cm wide at the bottom. The interior of the box was dividedequally by a vertical barrier into a light compartment (illuminated by a25-watt reflector lamp suspended 30 cm from the floor) and a darkcompartment (covered). There was a hole at the bottom of the barrier 2.5cm wide and 6 cm tall and a trap door which could be dropped to preventan animal from passing between the two compartments. A CoulbournInstruments small animal shocker was attached to two metal plates whichran the entire length of the apparatus, and a photocell was placed inthe dark compartment 7.5 cm from the vertical barrier and 2 cm off thefloor. The behavioral session was controlled by PDP 11/34 minicomputer.

At the end of the pretreatment interval, an animal was placed in thelight chamber directly under the light fixture, facing away from thedoor to the dark chamber. The apparatus was then covered and the systemactivated. If the mouse passed through the barrier to the darkcompartment and broke the photocell beam within 180 seconds, the trapdoor dropped to block escape to the light compartment and an electricshock was administered at an intensity of 0.4 milliamps for threeseconds. The animal was then immediately removed from the darkcompartment and placed in its home cage. If the animal failed to breakthe photocell beam within 180 seconds, it was discarded. The latency isseconds for each mouse was recorded.

Twenty-four hours later, the animals were again tested in the sameapparatus except that no injections were made and the mice did notreceive a shock. The test day latency in seconds for each animal wasrecorded and the animals were then discarded.

The high degree of variability (due to season of the year, housingconditions, and handling) found in one trial passive avoidance paradigmis well known. To control for this fact, individual cutoff (CO) valueswere determined for each test, compensating for interest variability.Additionally, it was found that 5 to 7% of the mice in thescopolamine/vehicle control groups were insensitive to scopolamine at 3mg/kg, sc. Thus, the CO value was defined as the second highest latencytime in the control group to more accurately reflect the 1/15 expectedcontrol responders in each test group. Experiments with a variety ofstandards repeated under a number of environmental conditions led to thedevelopment of the following empirical criteria: for a valid test, theCO value had to be less than 120 sec and the vehicle/vehicle controlgroup had to have at least 5/15 animals with latencies greater than CO.For a compound to be considered active the scopolamine/compound grouphad to have at least 3/15 mice with latencies greater than CO.

The results of the dark avoidance test are expressed as the number ofanimals per group (%) in which this scopolamine induced memory deficitis blocked as measured by an increase in the latency period. Relief ofmemory dysfunction activity for representative compounds of the presentinvention is presented in the Table.

                  TABLE                                                           ______________________________________                                                                    Percent of                                                                    Animals with                                                                  Scopolamine                                                                   Induced                                                            Dose       Memory Deficit                                    Compound         (mg/kg, sc)                                                                              Reversal                                          ______________________________________                                        1,3,9,10,11,12-Hexahydro-                                                                      1.0        36                                                2H-quino[4,3,2-ef][1,4]benz-                                                  oxazepin-2-one                                                                2,3,9,10,11,12-Hexahydro-                                                                      1.0        13                                                1H-quino[4,3,2-ef][1,4]benz-                                                  oxazepine, hydrochloride                                                      1-Benzyl-1,3,9,10,11,12-                                                                       3.0        27                                                hexahydro-2H-quino[4,3,2-ef]-                                                 [1,4]benzoxazepin-2-one                                                       2,3,9,10,11,12-Hexahydro-                                                                      1.0        27                                                3-phenyl-1H-quino[4,3,2-ef]                                                   [1,4]benzoxazepine                                                            ______________________________________                                    

Included among the compounds of the present inventions are:

a. 1-(2-bromoethoxy)-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine;

b.ethyl[(11-amino-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-1-yl)oxy]acetate;

c. 2,3,5,6-tetrahydro-1H-4-oxa-1,7-diazanaphth[3,2,1-cd]azulene;

d.1,9,10,11,12,13-hexahydrocyclohepta[5,6]pyrido[4,3,2-ef][1,4]benzoxazepin-2(3H)-one;

e.11-bromo-1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2ef][1,4]benzoxazepin-2-one;

f.10-methoxy-1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one;

g. 2,3,4a,5,6,7-hexahydro-9-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine;and

h.2,3,4a,5,6,7-hexahydro-10-trifluoromethyl-1H-quino[4,3,2,ef][1,4]benzoxazepine.

Scopolamine induced memory deficit reversal is achieved when the presentbenzoxazepines, -thiazepines, tetrahydroacridinamines, and relatedcompounds are administered to a subject requiring such treatment as aneffective oral, parenteral or intravenous dose of from 0.01 to 100 mg/kgof body weight per day. A particularly effective amount is about 25mg/kg of body weight per day. It is to be understood, however, that forany particular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The basic final products and intermediates, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

Similarly, the acidic intermediates may be formulated and administeredin the form of their pharmaceutically acceptable base addition saltssuch as, for example, salts of sodium, potassium, or calcium hydroxide,ammonium hydroxide and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution ofsuspension. These preparations should contain at least 0.5% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mg of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 1 1-[(2-Bromoethyl)oxy]-1,2,3,4-tetrahydro-9-acridinamine

To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (7.55 g) in 40ml of 2-bromoethanol was added 9.9 ml of trifluoroacetic acid. Thereaction mixture was stirred at ambient temperature for 18 hrs, added toiced sodium hydroxide solution, and the mixture was extracted with ethylacetate. The combined organic extracts were washed with water, saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,filtered, and evaporated. The residue was purified by flashchromatography (ethyl acetate→2% triethylamine/ethyl acetate) to give7.6 g (67%) of a product. Recrystallization from methanol/water gave theanalytical sample, mp 163.5°-164.5° C.

Analysis: Calculated for C₁₅ H₁₇ BrN₂ O: 56.08% C, 5.34% H, 8.72% N.Found: 56.27% C, 5.33% H, 8.63% N.

EXAMPLE 2 2,3,4a,5,6,7-Hexahydro-1H-quino-[4,3,2-ef][1,4]benzoxazepinehydrochloride

To a solution of 1-[(2-bromoethyl)oxy]-1,2,3,4-tetrahydro-9-acridinamine(4.1 g) in tetrahydrofuran (30 ml) was added potassium t-butoxide (1.72g). The reaction mixture was stirred at ambient temperature for 30 minsand then concentrated. The residue was partitioned between water andethyl acetate and the aqueous phase was extracted twice with ethylacetate. The combined organic extracts were washed with water, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated to give 2.85 g (92% of basic product. The basic product wasdissolved in methanol and treated with ethereal hydrogen chloride. Etherwas added. The precipitate was collected and recrystallized frommethanol/ethyl ether to give product, m.p. 242°-244° C. (dec.).

Analysis: Calculated for C₁₅ H₁₆ N₂ O.HCl: 65.09% C, 6.19% H, 10.12% N.Found: 64.76% C, 6.17% H, 10.08% N.

EXAMPLE 3 9-Benzylamino-1-[(2-bromethyl)oxy]-1,2,3,4-tetrahydroacridine

To a suspension of 9-benzylamino-1,2,3,4-tetrahydroacridin-1ol (7.20 g)in 2-bromoethanol (45 ml) was added 40 drops of trifluoroacetic acid.The reaction mixture was stirred at ambient temperature for 20 mins,added to iced sodium bicarbonate solution, and the suspension wasextracted with ethyl acetate. The combined organic extracts were washedwith water, saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered, and evaporated. The residue was purified byflash chromatography (ethyl acetate→1% triethylamine/ethyl acetate) togive 6.85 g (71%) of product. Recrystallization from cyclohexane gavethe analytical sample, mp 89°-91° C.

Analysis: Calculated for C₂₂ H₂₃ BrN₂ O: 64.24% C, 5.64% H, 6.81% N.Found: 64.23% C, 5.65% H, 6.77% N.

EXAMPLE 41-Benzyl-2,3,4a,5,6,7-hexahydro-1H-quino-[4,3,2-ef][1,4]benzoxazepinefumarate

To a solution of9-benzylamino-1-[(2-bromoethyl)oxy]-1,2,3,4-tetrahydroacridine (4.4 g)in tetrahydrofuran (30 ml) was added potassium t-butoxide (1.3 g). Thereaction was stirred at ambient temperature for 2 hrs, and thenconcentrated. The residue was partitioned between water and ethylacetate and the aqueous phase was extracted twice with ethyl acetate.The combined organic extracts were washed with water, saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. The residue was purified by flashchromatography to give 3.2 g (91%) of product. The product was dissolvedin ethyl ether and treated with an ethereal solution of fumaric acid togive the fumarate, mp 180°-182° C. (dec.).

Analysis: Calculated for C₂₂ H₂₂ N₂ O.C₄ H₄ O₄ : 69.94% C, 5.8% H, 6.28%N. Found: 69.71% C, 5.82% H, 6.22% N.

EXAMPLE 5 Methyl[(9-amino-1,2,3,4-tetrahydroacridin-1-yl)oxy]acetate

To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (28.8 g) andmethyl glycolate (81.2 g), cooled in an ice bath, was slowly added concsulfuric acid (20 ml). Ice-water was added. The mixture was washed withether, and the aqueous phase basified with sodium hydroxide solution,extracted with ethyl acetate, dried over anhydrous magnesium sulfate,and filtered. The filtrate was concentrated and the residue was purifiedby flash chromatography (10% triethylamine/toluene) to give 10.9 (28.4%)of product, mp 157°-163° C.

EXAMPLE 61,3,4a,5,6,7-Hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one

To a solution of methyl[(9-amino-1,2,3,4-tetrahydroacridin-1-yl)oxy]acetate (13.7 g) intetrahydrofuran (200 ml) was added potassium t-butoxide (6.7 g). Thereaction mixture was stirred at ambient temperature for 2.5 hrs andevaporated. The residue was stirred in dilute potassium carbonatesolution/ethyl ether. The precipitate was collected and dried. A 3.5 gsample was recrystallized twice from methanol/water, passed through acolumn of basic alumina (5% methanol/ethyl acetate) and recrystallizedfrom methanol to give 1.37 g (39%) of product, mp 173°-175° C.

Analysis: Calculated for C₁₅ H₁₄ N₂ O₂ : 70.85% C, 5.55% H, 11.02% N.Found: 70.90% C, 5.48% H, 10.95% N.

EXAMPLE 72,3,4a,5,6,7-Hexahydro-1-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepinemaleate hydrate

To a solution of1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (4.09g) in tetrahydrofuran (100 ml) was added potassium t-butoxide (2.17 g)followed by methyl iodide (1.25 ml). The reaction mixture was stirred inwater/ethyl ether, the precipitate was collected and dried to give 2.0 g(46%) of1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

A solution of lithium aluminum hydride (1M in tetrahydrofuran, 15.0 ml)was diluted with 50 ml of tetrahydrofuran. Aluminum chloride (2.0 g) wasadded in portions followed by1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(3.35 g). The reaction mixture was stirred for 45 mins and then pouredinto iced dilute sodium hydroxide solution. The aqueous phase wasextracted with ethyl acetate and the combined organic extracts werewashed with water, saturated sodium chloride solution, dried overanhydrous magnesium sulfate and filtered. Concentration of the filtrategave 3.1 g (97%) basic product. The basic product was dissolved inmethanol, maleic acid (1.1. eq) was added, followed by ether. Theprecipitate was recrystallized from methanol/ethyl ether to giveproduct, mp 166°-168° C. (dec.).

Analysis: Calculated for C₁₆ H₁₈ N₂ O.C₄ H₄ O₄.H₂ O: 61.84% C, 6.23% H,7.21%. Found: 61.94% C, 6.11% H, 7.26%.

EXAMPLE 8 Methyl[(9-amino-1,2,3,4-tetrahydroacridin-1yl)thio]acetate

To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.82 g) andmethyl thioglycolate (40 ml) was added 40 drops of sulfuric acid. Thereaction mixture was stirred at ambient temperature for 3 hrs, pouredinto an iced sodium bicarbonate solution, and extracted with ethylacetate. The combined organic extracts were washed with water, saturatedsodium chloride, and dried over anhydrous magnesium sulfate. Thefiltrate was concentrated in vacuo and the residue was triturated withethyl ether to give 2.79 g of product, mp 175°-183° C. (dec.).Recrystallization from methanol/water gave the analytical sample, mp194°-196° C. (dec.)

Analysis: Calculated for C₁₆ H₁₈ N₂ O₂ S: 63.55% C, 6.00% H, 9.27% N.Found: 63.42% C, 6.00% H, 9.23% n.

EXAMPLE 91,3,4a,5,6,7-Hexahydro-2H-quino[4,3,2-ef]]1,4]benzthiazepine-2-one

To a solution of methyl[(9-amino-1,2,3,4-tetrahydroacridin-1-yl)thio]acetate (10.3 g) intetrahydrofuran (150 ml) was added potassium t-butoxide (4.6 g). Thereaction mixture was stirred at ambient temperature for 45 mins and thenconcentrated. The residue was stirred in water, the solid was collected,and dried. The solid was purified by flash chromatography (ethylacetate/dichloromethane→5% methanol/dichloromethane) to give 4.1 g (44%)of product, mp 223°-226° C. (dec.). Recrystallization from methanol gavethe analytical sample, mp 223.5°-226° C. (dec.).

Analysis: Calculated for C₁₅ H₁₄ N₂ OS; 66.64%C, 5.22%H, 10.36%N. Found66.28%C, 5.13%H, 10.20%N.

EXAMPLE 10 2,3,4a,5,6,7-Hexahydro-1H-quino-[4,3,2-ef][1,4]benzthiazepine

To a solution of lithium aluminum hydride (30 ml of a 1M solution intetrahydrofuran diluted to 130 ml with tetrahydrofuran) was addedaluminum chloride (3.94 g). The mixture was stirred for 30 mins and then1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]benzthiazepin-2-one (6.65g) was added. The reaction mixture was stirred for 1 hr and then pouredinto 60 ml of 10% sodium hydroxide solution. The aqueous phase wasextracted with ethyl acetate and the combined organic extracts werewashed with water, saturated sodium chloride, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was preadsorbed on silicaand purified by flash chromatography (2% triethylamine/ethyl acetate) togive 3.0 g (48%) of product, mp 171°-175° C. Recrystallization frommethanol/water gave the analytical sample, mp 175°-177° C.

Analysis: Calculated for C₁₅ H₁₆ N₂ S: 70.27%C, 6.29%H, 10.93%N. Found:70.25%C, 6.14%H, 10.81%N.

EXAMPLE 11 [(9-Amino-1,2,3,4-tetrahydroacridin-1-yl)thio]acetic acidhydrochloride

In an experiment following the procedure of Example 9, the filtrate wasacidified with hydrochloric acid. The solid was collected, washed withwater and dried overnight at 60° C. to give 82% yield of product. Aportion of the product was dissolved in hot water and concentratedhydrochloric acid (10 ml) was added. The precipitate was collected,washed with water, and dried to give the analytical sample, mp 268°-269°C. (dec).

Analysis: Calculated for C₁₅ H₁₆ N₂ O₂ S.HCl: 55.46%C, 5.28%H, 8.63%N.Found: 55.31%C, 5.11%H, 8.55%N.

EXAMPLE 122,3,4a,5,6,7-Hexahydro-1-methyl-1H-quino-[4,3,2-ef][1,4]benzthiazepinemaleate

To a mixture of methyl[(9-amino-1,2,3,4-tetrahydroacridin-1-yl)thio]acetate (5.06 g) intetrahydrofuran (100 ml) was added potassium t-butoxide (2.3 g). Themixture was stirred for 30 mins and methyl iodide (1.6 ml) was added.Stirring was continued for 2 hrs, and the reaction mixture was pouredinto water. The aqueous phase was extracted three times with ethylacetate. The combined organic extracts were purified by flashchromatography (ethyl acetate/dichloromethane) to give 3.42 g (72%) ofthe1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino-[4,3,2-ef][1,4]benzthiazepin-2-one,mp 241°-245° C. (dec.).

To 1M lithium aluminum hydride in tetrahydrofuran (14.1 ml), dilutedwith tetrahydrofuran (50 ml) was added aluminum chloride (1.9 g),followed by1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino-[4,3,2-ef][1,4]benzthiazepin-2-one(3.42 g). After stirring for 1 hr, the reaction mixture was poured intoiced sodium hydroxide solution and extracted three times with ethylacetate. The combined organic extracts were washed with water, saturatedsodium chloride solution, and dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was dissolved in methanol andtreated with maleic acid (1.1 eq). Crystallization with ethyl etherfollowed by recrystallization from methanol/ethyl ether gave 3.17 g(73.0%) of product, mp 200°-201° C. (dec).

Analysis: Calculated for C₁₆ H₁₈ N₂ S.C₄ H₄ O₄ : 62.15%C, 5.74%H,7.25%N. Found: 62.07%C, 5.29%H, 7.16%N.

EXAMPLE 13 8-Methoxy-1,2,3,4-tetrahydro-9-acridinamine

6-Methoxyanthranilonitrile (14.0 g) was dissolved in nitrobenzene (150ml) and cyclohexanone (18.45 g), and freshly fused zinc chloride (25.6g) was added. The reaction mixture was warmed at 125° C. for 1.5 hr,cooled to room temperature, and poured into ether (1 l). The solid wascollected, washed with ether, and distributed between 2-butanone andammonium hydroxide. The organic phase was washed with brine, dried,filtered, and evaporated. The residue was recrystallized two times fromethyl acetate to give 13.7 g (63.8%), mp 187°-188° C.

Analysis: Calculated for C₁₄ H₁₆ N₂ O: 73.66%C, 7.06%H, 12.27%.N. Found:73.77%C, 7.11%H, 12.32%N.

EXAMPLE 14 8-Hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride

8-Methoxy-1,2,3,4-tetrahydro-9-acridinamine (4.0 g) was dissolved indichloromethane (76 ml). Boron tribromide in dichloromethane (15.0 ml ofa 1.0M solution) was added, and the reaction mixture was stirred 1 hrand then concentrated under reduced pressure. The residue was dissolvedin warm water (100 ml), concentrated hydrochloric acid (400 ml) wasadded and the solution was chilled overnight in the refrigerator. Thesalt was collected and recrystallized from methanol-ether to give 2.68 g(61%) of product, mp 270° C. (dec).

Analysis: Calculated for C₁₃ H₁₄ N₂ O.HCl: 62.27%C, 6.03%H, 11.18%N.Found: 62.35%C, 6.02%H, 11.05%N.

EXAMPLE 15 Ethyl[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]acetate

8-Hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride (18.07 g) wassuspended in 500 ml of dry dimethylformamide. Potassium carbonate (22.6g) was added, and the reaction mixture was stirred vigorously for 30mins. Ethyl bromoacetate (18.0 g) was added dropwise, and the reactionwas stirred vigorously overnight. The reaction mixture was distributedbetween ethyl acetate and water, and the organic layer was separated.The aqueous phase was extracted three times with ethyl acetate, and thecombined organic phase was washed with water, dried, filtered, and thefiltrate evaporate. The residue was purified by flash chromatography(ethyl acetate, then 5% triethylamine/ethyl acetate) to give 15.75 g(72.91%) of product, mp 141°-142° C.

Analysis: Calculated for C₁₇ H₂₀ N₂ O₃ : 67.98%C, 6.71%H, 9.33%N. Found:68.07%C, 6.71%H, 9.26%N.

EXAMPLE 161,3,9,10,11,12-Hexahydro-2-H-quino-[4,3,2-ef][1,4]benzoxazepin-2-one

Ethyl[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]acetate (14.50 g) wasdissolved in dry tetrahydrofuran (350 ml) and potassium t-butoxide (6.0g) was added. After stirring for 1 hr, 100 ml saturated ammoniumchloride solution (100 ml) was added, and stirring was continued for 30min. The reaction mixture was evaporated under reduced pressure. Thesolid was collected and washed with water to give 10.15 g (82.65%) ofproduct, mp 201°-202° C.

Analysis: Calculated for C₁₅ H₁₄ N₂ O₂ : 70.85%C, 5.55%H, 11.02%N.Found: 70.91%C, 5.62%H, 10.92%N.

EXAMPLE 17 2,3,9,10,11,12-Hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepinehydrochloride

1,3,9,10,11,12-Hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.00g) was suspended in dry tetrahydrofuran (100 ml) and 1Mborane/tetrahydrofuran (16.0 ml) was added. After 2 hrs, an additional30 ml of 1M borane/tetrahydrofuran was added, and the reaction mixturewas stirred overnight. The reaction mixture was poured into 5%hydrochloric acid and stirred unit hydrogen evolution ceased. Theorganic layer was separated and the aqueous phase was washed once withethyl acetate. The aqueous phase was basified with 10% sodium hydroxidesolution and precipitate was collected. The precipitate was treated withmethanol/ether/hydrogen chloride. Recrystallized from methanol/ethergave 2.50 g (57.5%) of product, mp 300° C. (dec).

Analysis: Calculated for C₁₅ H₁₆ N₂ O.HCl: 65.10%C, 6.19%H, 10.12%N.Found: 64.79%C, 6.22%H, 10.00%N.

EXAMPLE 181,3,9,10,11,12-Hexahydro-1-methyl-2H-quino[4,3,2,-ef][1,4]benzoxazepin-2-on

To a suspension of1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.0g) in dry tetrahydrofuran (120 ml) was added potassium tert-butoxide(1.94 g). The mixture was stirred at room temperature for 15 mins,iodomethane (1.08 ml) was added, and the reaction mixture was stirred atroom temperature overnight. The reaction mixture was concentrated,saturated potassium carbonate solution (150 ml) was added, and mixturewas extracted twice with 150 ml portions of ethyl acetate. The organicphase was washed with brine, dried over anhydrous magnesium sulfate,filtered, concentrated. Trituration with diethyl ether/pentane gave 3.47g (82%) of product. Recrystallization from methanol gave the analyticalsample, mp 176.5°-177.5° C.

Analysis: Calculated for C₁₆ H₁₆ N₂ O₂ : 71.62%C, 6.01%H, 10.44%N.Found: 71.42%C, 6.01%H, 10.38%N.

EXAMPLE 192,3,9,10,11,12-Hexahydro-1methyl-1H-quino-[4,3,2-ef][1,4]benzoxazepine

To a solution of lithium aluminum hydride in tetrahydrofuran (1.0M,15.82 ml) and dry tetrahydrofuran (32 ml) was added aluminum chloride(2.10 g) in portions. The mixture was stirred for five mins,1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.24 g) was added and the mixture was stirred at room temperatureovernight. The reaction mixture was quenched with ethyl acetate (150ml), 10% sodium hydroxide solution was added, and the organic layer wasseparated. The organic layer was washed wit brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was adheredto silica (methanol) and flash chromatographed (30-50% ethylacetate/Hexane) to yield 3.61 g (89.6%) of product, mp 97°-98° C.

Analysis: Calculated for C₁₆ H₁₈ N₂ O: 75.56%C, 7.13%H, 11.01%N. Found:75.30%C, 7.09%H, 10.94%N.

EXAMPLE 201-Ethyl-2,3,9,10,11,12-Hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepinemaleate

To suspension of1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0g) in dry tetrahydrofuran (110 ml) was added potassium tert-butoxide(2.65 g). The mixture was stirred for 20 mins, bromoethane (5.88 ml) wasadded, and the reaction mixture was refluxed for 6.5 hrs. The reactionmixture was concentrated, diluted with saturated potassium carbonatesolution, and extracted with ethyl acetate. The organic extractions weredried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was adhered to silica and flash chromatographed (20% ethylacetate/hexane) to yield 4.53 g (82%) of1-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1.0M,14.33 ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride(1.91 g) in portions. The mixture was stirred for five mins,1-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.04 g) was added, and stirring was continued for two hrs. The reactionmixture was quenched with ethyl acetate (200 ml,) 10% sodium hydroxidesolution (200 ml) was added, and the organic layer was separated. Theorganic layer was dried over anhydrous magnesium sulfate, andconcentrated. Recrystallization of the residue from diethyl ether gave2.41 g (59%) of product, mp 70.5°-72° C. The maleate salt was formedfrom hot methanol and had mp 188° C. (dec.).

Analysis: Calculated for C₁₇ H₂₀ N₂ O.C₄ H₄ O₄ : 65.61%C, 6.29%H,7.29%N. Found: 65.62%C, 6.19%H, 7.25%N.

EXAMPLE 212,3,9,10,11,12-Hexahydro-1-propyl-1H-quino[4,3,2-ef][1,4]benzoxazepine

To a suspension of1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.94g) in dry tetrahydrofuran (150 ml) was added potassium tert-butoxide(2.62 g). The mixture was stirred for 15 mins, 1-bromopropane (7.07 ml)was added, and the reaction mixture was refluxed overnight. The reactionmixture was concentrated, diluted with saturated potassium carbonatesolution, and extracted with ethyl acetate. The organic extracts weredried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was to adhered to adhered to silica, and flashchromatographed (30% ethyl acetate/hexane). The appropriate fractionswere evaporated and the residue was triturated with diethyl ether toyield 4.39 g (76%) of1,3,9,10,11,12-hexahydro-1-propyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1.0M, 14.2ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.89 g)in portions. The mixture was stirred for five mins,1,3,9,10,11,12-hexahydro-1-propyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.2 g) was added, and stirring was continued overnight. The reactionmixture was quenched with ethyl acetate (200 ml), 10% sodium hydroxidesolution (200 ml) was added, and the organic layer was separated. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. The residue was recrystallized frompentane/diethyl ether to yield 2.85 g (71%) of product, mp 74.5°-75.5°C.

Analysis: Calculated for C₁₈ H₂₂ N₂ O: 76.56%C, 7.85%H, 9.92%N. Found:76.50%C, 7.88%H, 9.84%N.

EXAMPLE 221-Benzyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,2]benzoxazepin-2-one

To a suspension of1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.30g) in dry dimethylformamide (50 ml) was added potassium tert-butoxide(2.1 g). To the solution was added benzyl bromide (2.22 ml), andstirring was continued for five mins. The reaction mixture was dilutedwith water (150 ml) and extracted with diethyl ether. The organic phasewas washed with water, brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. Trituration of the residuewith pentane followed by recrystallization from methanol gave 2.42 g(41%) of product, mp 166°-167.5° C.

Analysis: Calculated for C₂₂ H₂₀ N₂ O₂ : 76.72%C, 5.85%H, 8.13%N. Found:76.72%C, 5.92%H, 8.12%N.

EXAMPLE 231-Benzyl-2,3,9,10,11,12-hexahydroquino[4,3,2-ef][1,4]benzeoxazepine

To a solution of1-benzyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.71 g) in dry tetrahydrofuran (200 ml) was added borane intetrahydrofuran (1M, 65 ml). The reaction mixture was stirred at roomtemperature overnight, quenched with 5% hydrochloric acid (500 ml), andstirred for an additional 2.5 hrs. The reaction mixture was cooled (0°C.), basified with 10% sodium hydroxide solution (500 ml), and extractedwith ethyl acetate (800 ml). The organic phase was washed with brine,dried over anhydrous magnesium sulfate, and concentrated.Recrystallization of the residue from methanol yielded 3.05 g (68%) ofproduct, mp 132°-133° C.

Analysis: Calculated for C₂₂ H₂₂ N₂ O: 79.97%C, 6.71%H, 8.48%N. Found:79.83%C, 6.73%H, 8.47%N.

EXAMPLE 241,3,9,10,11,12-Hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one

To a solution of 8-hydroxy-1,2,3,4-tetrahydro-9-acrdinaminehydrochloride (3.77 g) in dry dimethylformamide (100 ml) was addedpotassium carbonate (4.7 g), with stirring. After one hr, methyl2-bromopropionate (2.51 ml) was added and stirring was continuedovernight. The reaction mixture was diluted with water, extracted withethyl acetate, dried over anhydrous sodium sulfate, concentrated, andthe residue was flash chromatographed (ethyl acetate, then 5%triethylamine/ethyl acetate) to yield 4.05 g (86.7%) of methylα-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]propionate hydrate.

To a solution of the methylα-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]propionate hydrate (3.7g) in dry tetrahydrofuran (65 ml) was added potassium t-butoxide (1.62g). The reaction mixture was stirred at room temperature for one hr,saturated ammonium chloride solution (18.2 ml) was added, and stirringwas continued for one hr. The mixture was concentrated. The solution wascooled, the solid was collected, washed with water, and dried to yield2.90 g (90%) of product, mp 200° C. (dec).

Analysis: Calculated for C₁₆ H₁₆ N₂ O₂ : 71.62%C, 6.01%H, 10.44%N.Found: 71.78%C, 5.88%H, 10.36%N.

EXAMPLE 252,3,9,10,11,12-Hexahydro-3-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 15.82ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (2.10 g)in portions; with stirring. After 5 mins,1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.24) was added, and the reaction mixture was stirred at roomtemperature for four hrs. Ethyl acetate (200 ml) and 10% sodiumhydroxide solution (200 ml) were added. The organic phase was separated,dried over anhydrous magnesium sulfate, and concentrated. The residuewas adhered to silica and flash chromatographed (5%triethylamine/toluene. The appropriate fractions were concentrated andthe residue was triturated with diethyl ether to yield 2.48 g (62%) ofproduct, mp 169°-170.5° C.

Analysis: Calculated for C₁₆ H₁₈ N₂ O: 75.56%C, 7.13%H, 11.01%N. Found:75.57% C, 7.08%H, 10.95%N.

EXAMPLE 261,3-Dimethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine

To a suspension of1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one(5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide(3.15 g), with stirring. After 15 mins, methyl iodide (1.39 ml) wasadded, and the reaction mixture was stirred at room temperatureovernight. Additional methyl iodide (0.4 ml) was added. The reactionmixture was refluxed for two hrs, cooled, and concentrated. Saturatedpotassium carbonate solution was added and the mixture was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated, and the residue was adhered tosilica, and flash chromatographed (30-60% ethyl acetate/hexane). Theappropriate fractions were concentrated, and the residue was trituratedwith diethyl ether to give 4.21 g (80%) of1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 10.0ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.86 g)in portions, with stirring. The reaction mixture was stirred for fivemins and1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(3.95 g) was added. After stirring for 30 min, ethyl acetate (200 ml)and 10% sodium hydroxide solution (200 ml) were added, and the organiclayer was separated, dried over anhydrous magnesium sulfate andconcentrated. Recrystallization of the residue from diethylether/pentane gave 2.2 g (59%) of product, mp 125°-126.5° C.

Analysis: Calculated for C₁₇ H₂₀ N₂ O: 76.09%C, 7.51%H, 10.44%N. Found:75.85%C, 7.33%H, 10.36%N.

EXAMPLE 271-Benzyl-2,3,9,10,11,12-hexahydro-3-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine

To a suspension of1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(5.0 g) in dry dimethylformamide (60 ml) was added potassium t-butoxide(3.15 g), with stirring. After 15 mins, benzyl bromide (2.66 ml) wasadded, and the reaction mixture was stirred for two hrs. The reactionmixture was diluted with water (300 ml), extracted twice with 100ml-portions of diethyl ether, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was adhered to silica and flashchromatographed (10-30% ethyl acetate/hexane). The mixed fractions wereflash chromatographed (3% ethyl acetate/dichloromethane), and theappropriate fractions were combined, and concentrated. Trituration ofthe residue with (1/1-diethyl ether/pentane) gave 4.58 g (68%) of1-benzyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 12.2ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.62 g)in portions, with stirring. After five mins,1-benzyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.38 g) was added and stirring was continued overnight. Ethyl acetate(200 ml) and 10% sodium hydroxide solution (200 ml) were added, and theorganic layer was separated, dried over anhydrous sodium magnesiumsulfate, and concentrated. Recrystallization of the residue frommethanol/diethyl ether gave 2.82 g (67%) of product, mp 151.5°-153° C.

Analysis: Calculated for C₂₃ H₂₄ N₂ O: 80.20%C, 7.02%H, 8.13%N. Found:80.25% C, 7.13%H, 8.11%N.

EXAMPLE 281-Ethyl-2,3,9,10,11,12-hexahydro-3-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine

To a suspension of1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.82 g) in dry tetrahydrofuran (150 ml) was added potassiumtert-butoxide (2.42 g), with stirring. After 20 mins, bromoethane (5.37ml) was added, and the reaction mixture was refluxed overnight. Thereaction mixture was concentrated, diluted with saturated potassiumcarbonate solution, and extracted with ethyl acetate. The organicextracts were dried over anhydrous magnesium sulfate, concentrated, andthe residue was adhered to silica and flash chromatographed (30% ethylacetate/hexane). The appropriate fractions were concentrated.Trituration of the residue with diethyl ether/pentane (1/1) gave 4.51 g(85%) of1-ethyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 14.22ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.90 g)in portions, with stirring. After five mins,1-ethyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino]4,3,2-ef][1,4]benzoxazepin-2-one(4.21 g) was added and stirring was continued for 0.5 hr. The reactionmixture was quenched with ethyl acetate (200 ml) and 10% sodiumhydroxide solution (200 ml). The organic layer was separated, dried overanhydrous magnesium sulfate, filtered, and concentrated. Recrystallizedof the residue from diethyl ether/pentane gave 2.17 g (54%) of product,mp 101°-103° C.

Analysis: Calculated for C₁₈ H₂₂ N₂ O: 76.56%C, 7.85%H, 9.92%N. Found:76.85%C, 7.99%H, 9.92%N.

EXAMPLE 293-Ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one

To a solution of 8-hydroxy-1,2,3,4-tetrahydro-9-acridinaminehydrochloride (23.08 g) in dry dimethylformamide was added potassiumcarbonate (28.75 g), with stirring. After one hr, methyl-2-bromobutyrate(15.89 ml) was added dropwise and stirring was continued overnight. Thereaction mixture was diluted with water (1.5 l), and extracted withethyl acetate (2 l). The organic extracts were dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was flash chromatographed (ethyl, acetate, 5%triethylamine/ethyl acetate) to yield 30.34 g of ethylα-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]butyrate hydrate.

To a solution of ethylα-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]butyrate hydrate (30.34g) in dry tetrahydrofuran (370 ml) was added potassium t-butoxide (13g). The reaction mixture was stirred at room temperature for 1.5 hrs.Saturated ammonium chloride solution (150 ml) was added and stirring wascontinued for one hr. The mixture was concentrated and the concentratewas cooled. The solid was collected, washed with water, and dried toyield 21.26 g (78%) of product, mp 182°-183° C.

Analysis: Calculated for C₁₇ H₁₈ N₂ O₂ ; 72.32%C, 6.43%H, 9.92%N. Found:72.32%C, 6.41%H, 9.89%N.

EXAMPLE 303-Ethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepinefumarate

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 14.8ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.89 g)in portions, with stirring. After 5 mins,3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.0 g) was added, and the reaction mixture was stirred at roomtemperature overnight. Ethyl acetate (200 ml) and 10% sodium hydroxidesolution (200 ml) were added. The organic phase was separated, driedover magnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was flash chromatographed (5% triethylamine/toluene). Theappropriate fractions were concentrated and treated with fumaric acid togive 4.05 g (74%) of product, mp 210° C.

Analysis: Calculated for C₁₇ H₂₀ N₂ O.C₄ H₄ O₄ : 65.61%C, 6.29%H,7.29%N. Found: 65.56%C, 6.27%H, 7.26%N.

EXAMPLE 313-Ethyl-2,3,9,10,11,12-hexahydro-1-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepinefumarate

To a suspension of3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide(3.0 g), with stirring. After 20 mins, methyl iodide (1.66) was added,and the reaction mixture was stirred at room temperature overnight. Thereaction mixture was concentrated, diluted with saturated potassiumcarbonate solution, and extracted with 2-butanone. The organic extractswere dried over anhydrous magnesium sulfate and concentrated. Theresidue was adhered to silica (methanol) and flash chromatographed (50%ethyl acetate/hexane). The appropriate fractions were concentrated andthe residue was triturated with diethyl ether to give 3.59 g (68%) of3-ethyl-1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 11.99ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.6 g)in portions, with stirring. After five mins,3-ethyl-1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(3.55 g) was added, and stirring was continued for 0.5 hr. Ethyl acetate(200 ml) and 10% sodium hydroxide solution (200 ml) were added, theorganic layer was separated, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. The residue was flashchromatographed (1.5% triethylamine/toluene). The appropriate fractionswere concentrated and the residue was treated with fumaric acid followedby recrystallization from methanol to give 1.82 g (38%) of product, mp243° C. (dec.).

Analysis: Calculated for C₁₈ H₂₂ N₂ O.C₄ H₄ O₄ : 66.32%C, 6.58%H,7.03%N. Found: 66.34%C, 6.51%H, 7.01%N.

EXAMPLE 32 Methylα-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]phenylacetate hydrate

8-Hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride (2.50 g) wassuspended in dry dimethylformamide (20 ml). Potassium carbonate (3.0 g)was added, and the mixture was stirred vigorously for 30 mins. Methylα-bromophenylacetate (2.10 g) was added dropwise, and the reactionmixture was stirred overnight. Water was added and the precipitate wascollected. The residue was purified by flash chromatography (5%triethylamine-ethyl acetate). Evaporation of the appropriate fractionsfollowed by recrystallization of the residue fromdichloromethane-pentane gave 2.35 g (65.1%) of product, mp 185° C.(dec).

Analysis: Calculated for C₂₂ H₂₂ N₂ O₃.0.25 H₂ O: 72.00%C, 6.18%H,7.64%N. Found: 72.12%C, 6.28%H, 7.60%N.

EXAMPLE 331,3,9,10,11,12-Hexahydro-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one

Methyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl]phenylacetate hydrate(5.26 g) was dissolved dry tetrahydrofuran (100 ml) and potassiumtert-butoxide (1.70 g) was added. After stirring for 1 hr, saturatedammonium chloride solution (100 ml) was added, and stirring wascontinued for 30 min. The reaction mixture was evaporated and the solidwas collected and washed with water. Recrystallization fromdimethylformamide-water gave 3.69 g (77.0%) of product, mp 250° (dec).

Analysis: Calculated for C₂₁ H₁₈ N₂ O₂ : 76.34%C, 5.49%H, 8.48%N. Found:76.57%C, 5.50%H, 8.45%N.

EXAMPLE 342,3,9,10,11,12-Hexahydro-3phenyl-1H-quino[4,3,2-ef][1,4]benzoxazepine

A solution of lithium aluminum hydride in tetrahydrofuran (1M, 12.0 ml)was added to dry tetrahydrofuran (30 ml) followed by aluminum chloride(1.60 g). The mixture was stirred for 15 mins and1,3,9,10,11,12-hexahydro-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepine-2-one(3.30 g) was added, with stirring. After 30 mins, 10% sodium hydroxidesolution was added, and the mixture was extracted with ethyl acetate.The organic phase was dried over anhydrous magnesium sulfate, filtered,and evaporated. The residue was purified by flash chromatography (5%triethylamine-ethyl acetate). Evaporation of the appropriate fractionsfollowed by recrystallization of the residue fromdichloromethane-pentane gave 2.14 g (67.72%) of product, mp 194°-195° C.

Analysis: Calculated for C₂₁ H₂₀ N₂ O: 79.72%C, 6.37%H, 8.85%N. Found:79.67%C, 6.38%H, 8.86%N.

EXAMPLE 351,3,9,10,11,12-hexahydro-1-methyl-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one

1,3,9,10,11,12-hexahydro-1-methyl-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepinefumarate (4.20 g) was suspended in dry tetrahydrofuran (75 ml), chilledwith ice/water, and potassium tert-butoxide (1.50 g) was added. Themixture was stirred for 1 hr, methyl iodide (1.90 g) was added, and themixture was stirred overnight. The reaction mixture was poured intoammonium chloride solution, and the organic layer was separated. Theaqueous phase was extracted with ethyl acetate. The combined organicphase was dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated. Recrystallization of the residue from methanolgave 3.37 g (77%) of product, mp 188°-189° C.

Analysis: Calculated for C₂₂ H₂₀ N₂ O₂ : 76.72%C, 5,85%H, 8.14%N. Found:76.73%C, 5.89%H, 8.12%N.

EXAMPLE 362,3,9,10,11,12-Hexahydro-1-methyl-3-phenyl-1H-quino[4,3,2-ef][1,4]benzoxazepinemaleate

A solution of lithium aluminum hydride in tetrahydrofuran (1M, 14.0 ml)was added to dry tetrahydrofuran (30 ml) followed by aluminum chloride(1.86 g). The mixture was stirred for 15 mins and1,3,9,10,11,12-hexahydro-1-methyl-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.00 g) was added, with stirring. After 30 mins, 10% sodium hydroxidesolution was added, and the mixture was extracted with ethyl acetate.The organic phase was dried over anhydrous magnesium sulfate, filtered,and the filtrate was evaporated. The residue was purified by flashchromatography (5% triethylamine-ethyl acetate). The residue, obtainedby evaporation of the appropriate fractions, was treated with fumaricacid in methanol-ether. The solid was collected and recrystallized frommethanol-ether to give 4.05 g (56.7%) of product, m.p. 172°-173° C.

Analysis: Calculated for C₂₂ H₂₂ N₂ O.C₄ H₄ O₄ : 69.94%C, 5.87%H,6.27%N. Found: 70.01%C, 5.94%H, 6.25%N.

EXAMPLE 371-Benzyl-3-ethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine

To a solution of3-ethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine(5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide(3.0 g). The mixture was stirred for 15 mins, benzyl bromide (3.16 ml)was added, and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was heated at reflux for 1.5 hrs,allowed to cool, concentrated and diluted with saturated sodiumbicarbonate solution (250 ml). The mixture was extracted twice withethyl acetate (250 ml), and the organic extracts were dried overanhydrous magnesium sulfate, filtered, and concentrated. Trituration ofthe residue first with pentane and then diethyl ether, gave 4.65 g (71%)of1-benzyl-3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 11.75ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.57 g)in portions. The mixture was stirred for five mins.1-Benzyl-3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one(4.37 g) was added and stirring was continued for three hrs. Thereaction mixture was quenched with ethyl acetate (200 ml), 10% sodiumhydroxide solution (200 ml) was added, and the organic layer wasseparated, dried over anhydrous magnesium sulfate and concentrated.Trituration of the residue with pentane followed by recrystallizationfrom methanol gave 2.86 g (68%) of product, mp 147.5°-149° C.

Analysis: Calculated for C₂₄ H₂₆ N₂ O: 80.41%C, 7.31%H, 7.81%N. Found:80.55%C, 7.61%H, 7.84%N.

EXAMPLE 381,3-Diethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepinefumarate

To a solution of3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4benzoxazepin-2-one(4.98 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide(2.26 g). The mixture was stirred for 20 mins, bromoethane (5.0 ml) wasadded, and the reaction mixture was refluxed overnight. The reactionmixture was concentrated, diluted with sodium bicarbonate solution (250ml), and extracted twice with ethyl acetate (250 ml). The extracts weredried over anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated, and the residue was triturated first with pentane and thediethyl ether to give 4.40 g (80.3%) of1,3-diethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4benzoxazepin-2-one.

To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 12.87ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.72 g)in portions. The mixture was stirred for five mins.1,3-Diethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4benzoxazepin-2-one(4.17 g) was added and stirring was continued for 1.5 hrs. The reactionmixture was quenched with ethyl acetate (200 ml), 10% sodium hydroxidesolution was added and the organic layer was separated. The organiclayer was dried over anhydrous magnesium sulfate, filtered,concentrated, and the residue was triturated with pentane to giveproduct. The fumarate was formed with fumaric acid methanol/diethylether; yield 3.82 g (69%), mp 194° C. (dec).

Analysis: Calculated for C₂₃ H₂₈ N₂ O₅ : 66.97% C, 6.84% H, 6.79% N.Found: 67.05% C, 6.82% H, 6.80% N.

EXAMPLE 392,3,4a,5,6,7-Hexahydro-3-phenyl-1H-quino[4,3,2-ef][1,4]benzoxazepinehydrochloride

To a suspension of sodium hydride (5.6 g) in 300 ml of dimethylformamidewas added 9-amino-3,4-dihydroacridin-1(2H)one (24.6 g) followed bystyrene oxide (15.9 ml). The mixture was heated at 80° C. for 18 hrs.quenched with water, and the aqueous phase was extracted with ethylacetate. The organic phase was washed with water, saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated. The residue was passed through a columnof florisil and then purified by flash chromatography(dichloromethane/acetone, 3/1) to give 9.7 g (25%) of3,4-dihydro-9-[((2-hydroxy-2-phenyl)ethyl)amino]-1(2H)-acridinone.

To a suspension of3,4-dihydro-9-[((2-hydroxy-2-phenyl)ethyl)amino]-1(2H)-acridine (4.5 g)in 100 ml of tetrahydrofuran was added a solution of lithium aluminumhydride in tetrahydrofuran (1M, 13.5 ml). After stirring at ambienttemperature for 1 hr, the reaction mixture was quenched with water (0.5ml). The precipitate was collected, washed with warm tetrahydrofuran andthe filtrate was concentrated to give 4.05 g (90%) of1,2,3,4-tetrahydro-9-[((2-hydroxy-2-phenyl)ethyl)amino]-1-acridinol.

A mixture of1,2,3,4-tetrahydro-9-[((2-hydroxy-2-phenyl)ethyl)amino]-1-acridinol(4.05 g), and 5% sulfuric acid/trifluoroacetic acid solution (50 ml) wasstirred for 5 mins. The reaction mixture was quenched with ice-water andneutralized with a 10% sodium hydroxide solution. The aqueous phase wasextracted with ethyl acetate and the combined organic phase was washedwith water, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was concentrated and the residue was purified by flashchromatography (3→5→7% triethylamine/toluene) to give 1.4 g (37%) of amajor diastereomer and 0.84 g (22%) of a minor diastereomer. The majorisomer was dissolved in methanol and treated with an ethereal hydrogenchloride to give 2.05 g of product, mp 274°-275° C. (dec).

Analysis: Calculated for C₂₁ H₂₀ N₂ O.HCl: 71.48% C, 6.00% H, 7.94% N.Found: 71.02% C, 5.92% H, 7.86% N.

The minor isomer was dissolved in methanol and treated with an etherealhydrogen chloride solution. The salt was crystallized by the addition ofether to give 1.10 g of product, mp: 240° C. dec.

Analysis: Calculated for C₂₁ H₂₀ N₂ O.HCl.0.5H₂ O: 69.70% C, 6.13% H,7.74% N. Found: 69.58% C, 6.12% H, 7.47% N. ##STR8##

We claim:
 1. A compound of the formulawherein R¹ is H, loweralkyl, orbenzyl; R is a group of the formula ##STR9## wherein Y is H, H or O, R²is H, loweralkyl, or phenyl, and Z is O or S; wherein Z of the group ofthe formula ##STR10## is bound to either the A- or B-position of theheteroaromatic nucleus; X is H, halogen, loweralkoxy, loweralkyl, ortrifluoromethyl; and n is 1, 2, or 3; the pharmaceutically acceptablesalts thereof; and the optical isomers thereof.
 2. A compound accordingto claim 1 wherein Z of the group of the formula ##STR11## is bound tothe A-position of the heteroaromatic nucleus, and n is
 2. 3. A compoundaccording to claim 1 wherein Z of the group of the formula ##STR12## isbound to the B-position of the heteroaromatic nucleus, and n is
 2. 4. Acompound according to claim 2 wherein Y is H, H.
 5. A compound accordingto claim 2 wherein Y is O.
 6. A compound according to claim 3 wherein Yis H, H.
 7. A compound according to claim 3 wherein Y is O.
 8. Thecompound according to claim 4 which is2,3,4a,5,6,7-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine.
 9. Thecompound according to claim 4 which is1-benzyl-2,3,4a,5,6,7-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine.10. The compound according to claim 5 which is1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one. 11.The compound according to claim 4 which is2,3,4a,5,6,7-hexahydro-1-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.12. The compound according to claim 5 which is1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]benzthiazepin-2-one. 13.The compound according to claim 4 which is2,3,4a,5,6,7-hexahydro-1H-quino[4,3,2-ef][1,4]benzthiazepine.
 14. Thecompound according to claim 42,3,4a,5,6,7-hexahydro-1-methyl-1H-quino-[4,3,2-ef][1,4]benzthiazepine.15. The compound according to claim 7 which is1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one. 16.The compound according to claim 6 which is2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine.
 17. Thecompound according to claim 7 which is1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.18. The compound according to claim 6 which is2,3,9,10,11,12-hexahydro-1-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.19. The compound according to claim 6 which is1-ethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine.20. The compound according to claim 6 which is2,3,9,10,11,12-hexahydro-1-propyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.21. The compound according to claim 7 which is1-benzyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.22. The compound according to claim 6 which is1-benzyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine.23. The compound according to claim 7 which is1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.24. The compound according to claim 6 which is2,3,9,10,11,12-hexahydro-3-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.25. The compound according to claim 6 which is1,3-dimethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine.26. The compound according to claim 6 which is1-benzyl-2,3,9,10,11,12-hexahydro-3-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.27. The compound according to claim 6 which is1-ethyl-2,3,9,10,11,12-hexahydro-3-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.28. The compound according to claim 7 which is3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.29. The compound according to claim 6 which is3-ethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]benzoxazepine.30. The compound according to claim 6 which is3-ethyl-2,3,9,10,11,12-hexahydro-1-methyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.31. The compound according to claim 7 which is1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one. 32.The compound according to claim 6 which is2,3,9,10,11,12-hexahydro-3-phenyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.33. The compound according to claim 7 which is1,3,9,10,11,12-hexahydro-1-methyl-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.34. The compound according to claim 6 which is2,3,9,10,11,12-hexahydro-1-methyl-3-phenyl-1H-quino[4,3,2-ef][1,4]benzoxazepine.35. The compound according to claim 5 which is1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.36. The compound according to claim 5 which is1,3,9,10,11,12-hexahydro-1-methyl-2H-quino-[4,3,2-ef][1,4benzthiazepin-2-one.37. The compound according to claim 7 which is2-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.38. The compound according to claim 7 which is1,3,9,10,11,12-hexahydro-1-propyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2one.39. The compound according to claim 7 which is1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.40. The compound according to claim 7 which is1-benzyl-1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.41. The compound according to claim 7 which is1-ethyl-1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.42. The compound according to claim 7 which is3-ethyl-1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.43. A method of relieving memory dysfunction in mammals comprisingadministering to a mammal memory dysfunction relief, a memorydysfunction relieving effective amount of a compound of claim
 1. 44. Amemory dysfunction relieving composition comprising and adjuvant and asthe active ingredient, a memory dysfunction relieving effective amountof a compound of claim
 1. 45. A process for the preparation of acompound of the formula ##STR13## wherein R is a group of the formula##STR14## wherein Y is H, H or O, R² is H, loweralkyl, or phenyl, and Zis O or S; R¹ is H, loweralkyl, or benzyl; Z of the group of the formula##STR15## is bound to either the A- or B-position of the heteroaromaticnucleus; X is H, halogen, loweralkoxy, loweralkyl, or trifluoromethyl; nis 1, 2, or 3, which comprises contacting a compound of the formula##STR16## wherein R¹ is H, loweralkyl or benzyl; R³ is a group of theformula CH₂ CHR² Hal wherein R² is hydrogen, loweralkyl, or phenyl andHal is chloro, bromo, or iodo, or a group of the formula CHR² CO₂ R⁵wherein R² is as above and R⁵ is H of loweralkyl; Z is O or S; X is H,halogen, loweralkoxy, loweralkyl, or trifluoromethyl; N is 1, 2, or 3; Zof the group ZR³ is bound to either the A- or B-position of theheteroaromatic nucleus with a cyclizing agent.
 46. The process of claim45 wherein the cyclizing agent is an alkali metal alkoxide.
 47. Theprocess of claim 46 wherein the alkali metal alkoxide is potassiumtertiary butoxide.
 48. The process of claim 45 wherein a solvent isemployed.
 49. The process of claim 48 wherein the solvent is an etherealsolvent.
 50. The process of claim 49 wherein the ethereal solvent istetrahydrofuran.
 51. The compound of claim 6 which is1-benzyl-3-ethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4]-benzoxazepine.52. The compound of claim 6 which is1,3-diethyl-2,3,9,10,11,12-hexahydro-1H-quino[4,3,2-ef][1,4benzoxazepine.53. The compound of claim 4 which is 2,3,4a,5,6,7-3-phenyl-1H-quino4,3,2-ef][1,4]benzoxazepine.
 54. The compound of claim 7 which is1-benzyl-3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one.55. The compound of claim 7 which is1,3-diethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.